Print ISSN 2319-2003 | Online ISSN 2279-0780

IJBCP  International Journal of Basic & Clinical Pharmacology

doi: http://dx.doi.org/10.18203/2319-2003.ijbcp20150370
Research Article

A clinical trial of treatment of uncomplicated typhoid fever: efficacy of

ceftriaxone-azithromycin combination
Vishal P. Giri1*, Om P. Giri2, Anshuman Srivastava3, Chandan Mishra1, Ajay Kumar4,
Shubhra Kanodia5

1
Department of
Pharmacology, Teerthanker
Mahaveer Medical College
and Research Centre,
Moradabad, Uttar Pradesh,
India, 2Department of
Pulmonary Medicine,
Darbhanga Medical College
and Hospital, Darbhanga,
Bihar, India, 3Department
of Paediatrics, Teerthanker
Mahaveer Medical College
and Research Centre, ABSTRACT
Moradabad, Uttar Pradesh,
India, 4Department of Background: Typhoid fever is a systemic infection caused by Gram-negative
Medicine, Teerthanker bacterium Salmonella enterica serovar typhi (S. typhi). It is a major health problem in
Mahaveer Medical College India. It carries significant morbidity and mortality. Antimicrobial therapy is critical
and Research Centre, for the management of typhoid fever. Emergence of multidrug-resistant (MDR) and
Moradabad, Uttar Pradesh, nalidixic acid-resistant (NAR) strains of S. typhi has complicated therapy by limiting
India, 5Department of Oral treatment options. Hence, this study was conducted to evaluate the efficacy and
Medicine and Radiology, safety profile of ceftriaxone and azithromycin combination therapy in uncomplicated
Teerthanker Mahaveer Dental typhoid fever.
College and Research Centre, Methods: Adults patients of blood culture proven uncomplicated typhoid fever
Moradabad, Uttar Pradesh, admitted in the medicine ward of Teerthanker Mahaveer Medical College and
India Research Centre were treated with ceftriaxone intravenously (2 g daily for 14 days)
and azithromycin orally (500  mg daily for 7  days). Patients were clinically and
Received: 04 April 2015 bacteriologically evaluated during the study period and follow-up.
Accepted: 10 May 2015 Results: 96% cure rate was observed. No relapse was recorded.
Conclusion: Ceftriaxone-azithromycin combination may be considered as an
*Correspondence to: empirical therapy for treatment of uncomplicated typhoid fever in view of the
Dr. Vishal P. Giri, emergence of MDR and NAR strains of S. typhi.
Email: drvpgiri@gmail.com
Keywords: Typhoid fever, Ceftriaxone, Azithromycin
Copyright: © the author(s),
publisher and licensee Medip
Academy. This is an open-
access article distributed under
the terms of the Creative
Commons Attribution Non-
Commercial License, which
permits unrestricted non-
commercial use, distribution,
and reproduction in any
medium, provided the original
work is properly cited.

www.ijbcp.com International Journal of Basic & Clinical Pharmacology | July-August 2015 | Vol 4 | Issue 4  Page 673
 Giri VP et al. Int J Basic Clin Pharmacol. 2015 Aug;4(4):673-677
INTRODUCTION
Typhoid fever is an acute, generalized infection of the
reticuloendothelial system caused by Salmonella enterica
serovar typhi (S. typhi). It is most often acquired through
consumption of water or food that has been contaminated
by feces of acutely infected or convalescent person or
a chronic asymptomatic carrier. The onset of illness is
gradual. Fever increases daily from low-grade to as high
as 102-104°F (38-40°C) by the 3rd-4th day of illness. It
is associated with headache, malaise, and loss of appetite.
There may be hepatosplenomegaly and a macular rash on
the trunk. Life-threatening complications can occur after
2-3 weeks of illness. Diagnosis is made by blood, bone
marrow, or stool culture. Specific antimicrobial therapy
shortens the clinical course of typhoid fever and reduces
the risk of death.1
For decades, chloramphenicol has been highly effective
against S. typhi, but multi-drug resistant (MDR) strains
of S. typhi (resistant to chloramphenicol, trimethoprim-
sulfamethoxazole, and ampicillin) has restricted its use in
typhoid fever. Fluoroquinolones have proven to be effective
for MDR cases of typhoid fever.
However, nalidixic acid-resistant (NAR) isolates of S. typhi
have reduced susceptibility to fluoroquinolones, and hence
typhoid fever caused by these isolates responds less well to
fluoroquinolone therapy. Resistance to NA has been rising
in India since 2005 and is currently 100%.2,3
Ceftriaxone is highly effective in typhoid fever, but it is less
than ideal alternative drug for the treatment of uncomplicated
typhoid fever. It shows a slow response with mean time of
5-7 days or even longer to defervescence, which could be
attributed to poor penetration capability of the drug into
the cells, and thus difficult to eradicate the bacteria from
the intracellular niche. Extended spectrum beta-lactamase
(CTX-M-15 and SHV-12 ESBLs) and CMY-2-AmpC
beta-lactamase producing S. typhi has been reported. Rise
in resistance to third or fourth generation cephalosporins
has been observed in many studies. 4 Azithromycin
possesses many characteristics for effective and convenient
treatment of typhoid fever, and hence, it is a further option.
Azithromycin resistant strains of S. typhi has recently been
reported in India.5,6
Over last few years, preliminary published data have proven
combination therapy of intravenous ceftriaxone with oral
azithromycin significantly superior to ceftriaxone alone
albeit in a small group of non-immunized travellers who
acquired typhoid fever in the Indian subcontinent.
The current study goal is to examine the efficacy of
ceftriaxone and azithromycin combination therapy for the
treatment of uncomplicated typhoid fever.
 International Journal of Basic & Clinical Pharmacology | July-August 2015 | Vol 4 | Issue 4  Page 674
METHODS
The present prospective study was conducted in Teerthanker
Mahaveer Medical College and Research Centre, Moradabad,
Uttar Pradesh, India, during the period from March 2014 to
January 2015. The study was approved by Institutional Ethic
Committee.
Totally, 25 patients of typhoid fever admitted in the medicine
wards were selected for the study. In all cases, blood culture
was positive for S. typhi. Antimicrobial susceptibility
test (AST) of isolates to chloramphenicol, trimethoprim-
sulfamethoxazole, ampicillin, ciprofloxacin, ofloxacin,
ceftriaxone, and azithromycin was also performed. Blood
culture from patients was processed by BACTEC 9240
blood culture automated system (Becton Dickinson). ID
(identification) and AST were determined by BD Phoenix
100 automated microbiology system.
Routine investigations e.g., electrocardiogram,
echocardiography, and radiography (X-ray chest, sonography
chest, and abdomen), complete blood count, bone marrow
examination, serological test for malaria, urinalysis, liver
function tests, and renal function tests were done in each
patient.
Inclusion criteria
(a) Adult, (b) uncomplicated typhoid fever, (c) blood culture
positive for S. typhi, (d) isolates susceptible in vitro to
ceftriaxone and azithromycin, (e) signed informed consent
to participate in the study, (f) patient able to take oral
medications.
Exclusion criteria
(a) Allergy to cephalosporins or macrolides, (b) typhoid
fever associated with complications e.g., intestinal
perforation, intestinal bleeding, shock, and encephalopathy,
(c) inability to swallow oral medication, (d) underlying
illness, (e) pregnancy, (f) lactation, (g) treatment within the
past 4 days with an antibiotic that may be effective against
typhoid fever.
A specially designed proforma was prepared and data
pertaining to the patients were recorded in it. Data included
demographic details, symptoms and signs, clinical course
including temperature measurement, and outcome including
complications, relapse and bacteremia and disposition
(discharged, transferred, died).
All study group patients were treated with a combination
of intravenous ceftriaxone 2 g daily for 14 days with oral
azithromycin 500 mg daily for the first 7 days.
Supportive treatment included paracetamol tablet and
intravenous dextrose infusion when indicated. The patients
 Giri VP et al. Int J Basic Clin Pharmacol. 2015 Aug;4(4):673-677

were given semisolid diet to liquid balanced diet throughout Table 1: Age and sex distribution in the typhoid
the therapy. fever patients.
Age n (%)
Each day, every case was clinically evaluated twice daily
group Male Female Total
(morning and evening) in the ward and oral temperature
recorded. Blood culture was repeated at the end of treatment 18‑22 5 (20) 2 (8) 7 (28)
(day 14). Each patient remained hospitalized throughout 23‑27 6 (24) 2 (8) 8 (32)
the treatment period and next 3 days after therapy was 28‑32 4 (16) ‑ 4 (16)
completed. Patients were followed up once weekly for 33‑37 1 (4) 2 (8) 3 (12)
1-month after end of the therapy for relapse of symptoms.
38‑42 ‑ ‑ ‑
Stool cultures were performed after the treatment and
repeated at 1, 3 and 6 months later for S. typhi. 43‑47 1 (4) 2 (8) 3 (12)
Total 17 (68) 8 (32) 25 (100)
Primary outcomes of interest were: (a) Treatment failure, Mean age: 27.38±9.13 years
defined as persistence of fever after 7  days of treatment
or development of complications under the treatment,
(b) microbiological failure, defined as a positive culture Table 2: Duration of fever in the typhoid fever
from blood at the end of treatment, (c) relapse, defined as patients before starting treatment.
recurrence of symptoms in addition to a positive culture Duration Patients
from blood or stool within 1-month during follow-up period, of fever n (%)
(d) adverse drug reaction, defined as an injury related to ≤7 days 7 (28)
medical management, in contrast to complications of disease,
8‑14 days 16 (64)
(e) fecal carrier.
>14 days 2 (8)
Mean duration of fever: 9.20±3.86
Secondary outcomes included

(a) Fever clearance time (FCT), defined as time in hours
from the start of the trial drug until body temperature falls
to values <37.50°C and remains so for 48 hrs. (b) Duration
of hospital stay, defined as time in days from entry into trial
until discharge.
Patients were considered clinically cured when fever
subsided within 7 days of antibiotic therapy and without
any relapse during 1-month follow-up period.
Statistical analysis of data
All the data were calculated by SPSS software version 15.0.
The parametric variables were defined as mean ± standard
deviation.
RESULTS
carrier state was noted. Stool culture remained negative
during follow-up 6 months period in all treated cases. Cost
of ceftriaxone and azithromycin treatment in one patient
was 1830 INR.
DISCUSSION
Meltzer et al. conducted a comparative trial of
ceftriaxone  -  azithromycin combination therapy versus
ceftriaxone monotherapy on 37 patients suffering from
enteric fever (Salmonella paratyphi A infection) and
reported that combination therapy may provide therapeutic
advantage over monotherapy. Time to defervescence in
17  patients treated with ceftriaxone and azithromycin
combination was 3.2 days, whereas in 13 cases treated
with ceftriaxone monotherapy, the time to defervescence
was 6.6 days.

Totally, 17 out of the 25 patients were males (68%) with The present study conducted a trial of ceftriaxone and
a male to female ratio of 2.1:1. Age of all patients ranged azithromycin combination on 25  patients suffering from
between 18 and 47 years. Mean age of patients was typhoid fever caused by S. typhi observed defervescence
27.38 years (Table 1). in 4.88 days.

Mean duration of fever in the study group was 9.20 days
(Table 2). Mean time to become afebrile was 4.88 days. FCT
was <5 days in 23 (92%) and in 1 (4%) case fever settled
in 7 days. Treatment failure was observed in 1 (4%) case.
There was no relapse in cured cases (Tables 3-5).
Two patients (8%) experienced minor adverse effects:
nausea and pain abdomen and were managed easily. No
Treatment of typhoid fever has been complicated in recent
years by the rise of MDR strains including quinolone/NAR
S. typhi (NARST). The preferred regimen for NARST is a
10-14 days course of ceftriaxone.7
Antibiogram of S. typhi isolates from blood in coastal
Karnataka region of India revealed these strains to be highly
susceptible to ceftriaxone.8

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 Giri VP et al. Int J Basic Clin Pharmacol. 2015 Aug;4(4):673-677
Table 3: Response to therapy in the typhoid fever patients.
Total (n) Good response* (n) Moderate response** (n)
25 1 22
*Temperature settling in 3 days, **Temperature settling in 3‑5 days, ***Temperature settling in >5 days
Table 4: Reduction of body surface temperature (°F)
in the typhoid fever patients.
Days Temperature (°F)
Mean SD
Day 1 102.34 0.9
Day 3 99.90 0.7
Day 5 98.42 0.3
Day 7 98.20 0.2
SD: Standard deviation
Table 5: FCT in the typhoid fever patients.
Group Mean±SD
Typhoid fever patients 4.88±0.53 days
FCT: Fever clearance time, SD: Standard deviation
However, response to ceftriaxone is slow. Median time to
defervescence in more than 10 days has been reported in some
studies. The delayed response to it may reflect the intracellular
location of S. typhi, where ceftriaxone is less active.9
Jain and Das Chugh has recently reported resistance to
ceftriaxone in 1% strains of S. typhi, at Delhi, India. Garg
et al. noted 2.5% strains of S. typhi resistant to ceftriaxone
at Shimla, Himachal Pradesh, India.
Azithromycin has been reported to be as effective
as ceftriaxone in the treatment of typhoid fever. The
efficacy of azithromycin during treatment is related to
tissue concentration rather than serum concentration.10,11
Azithromycin is also rapidly cleared from circulation.
Azithromycin resistance leading to treatment failure has
been reported by Molloy et al.
Azithromycin resistance rate to S. typhi has increased from
2.6% to 17.6% in India. It is a matter of concern.12
Ceftriaxone exerts its maximum effect in the extracellular
compartment. The azithromycin shows excellent penetration
into most tissues, and it achieves concentration in
macrophages and neutrophils that are more than 100-fold
higher than the concentration in serum, so it exerts its
maximum effect in the intracellular compartment. Their
combination may confer additional benefit. Hence, a novel
approach was proposed to combine both the drugs for
treatment of typhoid fever.13-16
The combination of these two drugs (ceftriaxone and
azithromycin) has become standard practice in Israel. The
combination needs further trials for evaluation of efficacy
and safety profile in the Indian context, so that it might be
 International Journal of Basic & Clinical Pharmacology | July-August 2015 | Vol 4 | Issue 4  Page 676
Poor response*** (n) No response (n)
1 1
recommended as empirical therapy for treatment of typhoid
fever in endemic areas.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: This study was approved by Institutional
Ethics Committee
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Cite this article as: Giri VP, Giri OP, Srivastava A,
15. Sjölund-Karlsson M, Joyce K, Blickenstaff K, Ball T,
Mishra C, Kumar A, Kanodia S. A clinical trial of treatment
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